Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics

• Published in: The Journal of biological chemistry Vol. 276; no. 16; pp. 12822 - 12826
• Main Authors: Smirlis, D, Muangmoonchai, R, Edwards, M, Phillips, I R, Shephard, E A
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 20.04.2001
• Subjects: androstane receptors; Animals; Biolistics; Cells, Cultured; Chloramphenicol O-Acetyltransferase - biosynthesis; Chloramphenicol O-Acetyltransferase - genetics; CYP gene; CYP2B1 gene; CYP3A1 gene; Cytochrome P-450 CYP2B1 - biosynthesis; Cytochrome P-450 CYP2B1 - genetics; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Dimerization; Enzyme Induction - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Hepatocytes - cytology; Hepatocytes - enzymology; Mice; Mixed Function Oxygenases - biosynthesis; Mixed Function Oxygenases - genetics; Pregnane X Receptor; pregnane X receptors; Promoter Regions, Genetic; Rats; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - physiology; Receptors, Steroid - genetics; Receptors, Steroid - physiology; Recombinant Fusion Proteins - biosynthesis; Retinoid X Receptors; Salamandridae; Transcription Factors - genetics; Transcription Factors - physiology; Transcriptional Activation; Transfection; Xenobiotics - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M005930200

The mechanisms by which different classes of chemicals induce the same cytochrome P450 (CYP) or the same chemical differentially induces more than one CYP are not well understood. We show that in primary hepatocytes and in vivo in liver (transfected by particle-mediated delivery) two orphan nuclear receptors, constitutive androstane receptor and pregnane X receptor (PXR1), transactivate a CYP gene via the same response element in a xenobiotic-specific manner. The constitutive androstane receptor mediates the barbiturate activation of expression of CYP2B1 and CYP3A1 . PXR1 activates both genes in response to synthetic steroids. To exert their effect the receptors bind to the same direct repeat site (DR4) within the phenobarbital response element of the CYP2B1 promoter and to the same DR3 site in the pregnane X response element of CYP3A1 . The receptors are therefore promiscuous with respect to DNA binding but not ligand binding. Differences in enhancer half-site spacing may influence the efficiency of interactions between the receptor and the transcription machinery and hence form the basis for the differential induction of CYP2B1 and CYP3A1 in response to barbiturates and synthetic steroids.